There is a concerted effort by medical research toward understanding the neurochemical control of respiratory rhythm generating networks as well as the premotor and motoneuron circuits that determine activity patterns of respiratory muscles. Insights derived from experimental work are important for developing pharmacological interventions to alleviate respiratory depression in a variety of medical conditions. In this regard, a specific region within the ventrolateral medulla, the preBötzinger complex (preBötC) is a major region of investigative focus as playing a critical role in generating rhythmic inspiratory drive (reviewed in Feldman et al. (2006) Nat. Rev. Neurosci. 7(3):232-241).
Within the preBötC, glutamatergic synaptic signaling mediated by non-NMDA receptors (primarily α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors) is particularly important for maintaining respiratory rhythm. See, Greer J. J., et al. (1991)J. Physiol. 437:727-749; Funk, G. D., et al. (1993)J. Neurophysiol. 70(4):1497-1515. Block of non-NMDA receptors with the antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) causes a dose-dependent decline, and eventual cessation, of respiratory frequency and inspiratory drive to cranial and spinal motoneurons. Elevation of endogenously released glutamate levels with glutarnatergic uptake inhibitors (Funk, G. D., et al. (1993)) or reduction of AMPA receptor desensitization (see, Funk, G. D., et al. (1995) J. Neurosci. 15:4046-4056) leads to increases in respiratory frequency in vitro.
Opiates have long been known to disrupt respiratory rhythm and to depress breathing and respiratory sensitivity to CO2 (reviewed in Shook et al., (1990) Am. Rev. Respir. Dis. 142(4):895-909). The pons and medulla are known to be the primary sites where opiate drugs produce these respiratory effects (Id.). Endogenous opioids as well as μ- and δ-subtypes of opioid receptors are present in essentially all respiratory regions of the pons and medulla (Yeadon and Kitchen, (1989) Prog Neurobiol. 33(1):1-16). In vivo and in vitro investigations have shown that exogenous opioids depress inspiratory and expiratory neuronal activity postsynaptically (Denavit-Saubie', Champagnat and Zieglgansberger, (1978) Brain Res. 155(1):55-67.) as well as presynaptically (Johnson, Smith and Feldman, (1996) J. Appl. Physiol. 80(6):2120-33). The underlying cellular mechanisms responsible for the opiate effects on respiration have not, however, been elucidated.
Opiate agents are widely used in medicine. Because they depress breathing, however, their use is contraindicated in many instances, especially in patients with compromised cardiovascular and pulmonary function. Thus, there has been a long-felt need to harness the analgesic power of the opiates and opioids, without depressing the respiratory function of the patient.
The present invention addresses this and other needs by disclosing that positive allosteric AMPA receptor modulators provide a novel pharmacological means of countering respiratory depression. The present invention demonstrates that a positive allosteric AMPA receptor modulator, which can potentiate AMPA receptor-mediated currents (Nagarajan, N., et al. (2001) Neuropharmacol. 41:650-663) is an effective means of countering respiratory depression.